The amino acids and carbohydrates that are oxidized for energy are transported between the tissues and organs by well-defined inter-organ transport cycles. In general, these cycles are arranged so that a metabolic product released from one organ is absorbed and oxidized by another. For example, glutamine released from skeletal muscle into the venous blood is absorbed and oxidized to CO2 by the intestinal mucosa. Recent in vitro experiments have suggested that glutamine and the ketone bodies are the major respiratory fuels for fast-growing, undifferentiated tumors. Mitochondria from these tumors contain a kidney-type, phosphate-dependent glutaminase and an NAD(P)-dependent malic enzyme, the enzymes required for the net oxidation of glutamine, and succinyl CoA:acetoacetate CoA transferase, the enzyme necessary for ketone body oxidation. The activities of these enzymes are low in normal liver and the slow-growing hepatomas but high in fast-growing, undifferentiated hepatomas. Consequently, new enzyme synthesis occurs during tumor progression in hepatomas. We propose that a common pattern of substrate utilization for energy production is adopted by all undifferentiated tumors. The pattern is characterized by the oxidation of glutamine and ketone bodies as the major respiratory fuels. The objective of this research is to test this hypothesis in vivo using a series of transplanted hepatomas and other tumors of varying growth rates and degrees of differentiation. A clearer understanding of energy production in tumors, the changes in energy production that occur during tumor progression, and the inter-relationship between tumor and host will result.